Method for treating excessive aggression

ABSTRACT

The invention provides a method for treating extreme aggression in a mammal comprising administering an effective amount of olanzapine, or a pharmaceutically acceptable salt or solvate thereof, to the mammal.

This is a 371 of PCT/US96/19573 filed Dec. 4, 1996.

This invention provides a method for using2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine,(hereinafter referred as "olanzapine"), for the treatment of excessiveaggression.

Excessive agression can be a problem for institutionalized patients andmay be associated with violent suicides. Extreme aggressiveness can beharmful to the individual prone to extreme aggressivenes, may bedetrimental to relationships and family members interacting with theindividual, and may complicate the management of patients or prisonersin the institutional setting.

Studies of animals and human beings suggest that 5-HT serves a criticalrole in aggression and impulsivity. Several human studies report acorrelation between low cerebrospinal fluid 5-HIAA and violent suicides.Therefore, extreme aggression appears to be associated withabnormalities in 5-HT. Goodman and Gillman, The Parmacololgical Basis ofTherapeutics, 257 (9th Ed. McGraw-Hill, New York, 1996). However, thereis a need for new treatments that can manage extreme aggression in asafe and ethical manner.

It is known that olanzapine can provide antipsychotic activity and iscurrently undergoing investigation for this purpose. Olanzapine is aknown compound and described in U.S. Pat. No. 5,229,382 as being usefulfor the treatment of schizophrenia, schizophreniform disorder, acutemania, mild anxiety states, and psychosis. U.S. Pat. No. 5,229,382 isherein incorporated by reference in its entirety. However, olanzapinewas not known to be useful for the treatment of excessive aggression.Applicants have discovered that olanzapine can be useful for thetreatment of extreme aggression. Olanzapine could address a long feltneed for treatments which provides a favorable safety profile andeffectively provides relief for the patient or individual suffering fromextreme aggression.

The presently claimed invention provides a method for treating extremeaggression, comprising administering an effective amount of olanzapineor a pharmaceutically acceptable salt thereof to a patient in need ofsuch treatment.

The present invention provides a method for treating excessiveaggression in a mammal, wherein the mammal is not clinically diagnosedas suffering from a psychotic condition.

Olanzapine is of the formula ##STR1## or an acid addition salt thereof.

It is especially preferred that olanzapine will be the Form IIolanzapine polymorph having a typical x-ray powder diffraction patternas represented by the following interplanar spacings:

    ______________________________________                                        ______________________________________                                        10.2689                                                                         8.577                                                                         7.4721                                                                        7.125                                                                         6.1459                                                                        6.071                                                                         5.4849                                                                        5.2181                                                                        5.1251                                                                        4.9874                                                                        4.7665                                                                        4.7158                                                                        4.4787                                                                        4.3307                                                                        4.2294                                                                        4.141                                                                         3.9873                                                                        3.7206                                                                        3.5645                                                                        3.5366                                                                        3.3828                                                                        3.2516                                                                        3.134                                                                         3.0848                                                                        3.0638                                                                        3.0111                                                                        2.8739                                                                        2.8102                                                                        2.7217                                                                        2.6432                                                                        2.6007                                                                      ______________________________________                                    

A typical example of an x-ray diffraction pattern for Form II is asfollows wherein d represents the interplanar spacing and I/I₁ representsthe typical relative intensities:

    ______________________________________                                                d     I/I.sub.1                                                       ______________________________________                                                10.2689                                                                             100.00                                                            8.577       7.96                                                              7.4721        1.41                                                            7.125       6.50                                                              6.1459        3.12                                                            6.071       5.12                                                              5.4849        0.52                                                            5.2181        6.86                                                            5.1251        2.47                                                            4.9874        7.41                                                            4.7665        4.03                                                            4.7158        6.80                                                            4.4787       14.72                                                            4.3307        1.48                                                            4.2294       23.19                                                            4.141       11.28                                                             3.9873        9.01                                                            3.7206       14.04                                                            3.5645        2.27                                                            3.5366        4.85                                                            3.3828        3.47                                                            3.2516        1.25                                                            3.134        0.81                                                             3.0848        0.45                                                            3.0638        1.34                                                            3.0111        3.51                                                            2.8739        0.79                                                            2.8102        1.47                                                            2.7217        0.20                                                            2.6432        1.26                                                            2.6007        0.77                                                          ______________________________________                                    

The x-ray diffraction patterns set out herein were obtained using aSiemens D5000 x-ray powder diffractometer having a copper K.sub.αradiation source of wavelength, λ=1·541 Å.

It is further preferred that the Form II olanzapine polymorph will beadministered as the substantially pure Form II olanzapine polymorph.

As used herein "substantially pure" refers to Form II associated withless than about 5% Form I, preferably less than about 2% Form I, andmore preferably less than about 1% Form I. Further, "substantially pure"Form II will contain less than about 0.5% related substances, wherein"related substances" refers to undesired chemical impurities or residualsolvent or water. In particular, "substantially pure" Form II shouldcontain less than about 0.05% content of acetonitrile, more preferably,less than about 0.005% content of acetonitrile. Additionally, the FormII polymorph should contain less than 0.5% of associated water.

The polymorph obtainable by the process taught in the '382 patent willbe designated as Form I and has a typical x-ray powder diffractionpattern substantially as follows, obtained using a Siemens D5000 x-raypowder diffractometer, wherein d represents the interplanar spacing:

    ______________________________________                                        ______________________________________                                        9.9463                                                                          8.5579                                                                        8.2445                                                                        6.8862                                                                        6.3787                                                                        6.2439                                                                        5.5895                                                                        5.3055                                                                        4.9815                                                                        4.8333                                                                        4.7255                                                                        4.6286                                                                        4.533                                                                         4.4624                                                                        4.2915                                                                        4.2346                                                                        4.0855                                                                        3.8254                                                                        3.7489                                                                        3.6983                                                                        3.5817                                                                        3.5064                                                                        3.3392                                                                        3.2806                                                                        3.2138                                                                        3.1118                                                                        3.0507                                                                        2.948                                                                         2.8172                                                                        2.7589                                                                        2.6597                                                                        2.6336                                                                        2.5956                                                                      ______________________________________                                    

A typical example of an x-ray diffraction pattern for Form I is asfollows wherein d represents the interplanar spacing and I/I₁ representsthe typical relative intensities:

    ______________________________________                                                d     I/I.sub.1                                                       ______________________________________                                                9.9463                                                                              100.00                                                            8.5579       15.18                                                            8.2445        1.96                                                            6.8862       14.73                                                            6.3787        4.25                                                            6.2439        5.21                                                            5.5895        1.10                                                            5.3055        0.95                                                            4.9815        6.14                                                            4.8333       68.37                                                            4.7255       21.88                                                            4.6286        3.82                                                            4.533       17.83                                                             4.4624        5.02                                                            4.2915        9.19                                                            4.2346       18.88                                                            4.0855       17.29                                                            3.8254        6.49                                                            3.7489       10.64                                                            3.6983       14.65                                                            3.5817        3.04                                                            3.5064        9.23                                                            3.3392        4.67                                                            3.2806        1.96                                                            3.2138        2.52                                                            3.1118        4.81                                                            3.0507        1.96                                                            2.948        2.40                                                             2.8172        2.89                                                            2.7589        2.27                                                            2.6597        1.86                                                            2.6336        1.10                                                            2.5956        1.73                                                          ______________________________________                                    

The x-ray powder diffraction patterns herein were obtained with a copperK.sub.α of wavelength λ=1.541 Å. The interplanar spacings in the columnmarked "d" are in Angstroms. The typical relative intensities are in thecolumn marked "I/I₁ ".

As used herein, the term "mammal" shall refer to the Mammalia class ofhigher vertebrates. The term "mammal" includes, but is not limited to, ahuman. The term "treating" as used herein includes prophylaxis of thenamed condition or amelioration or elimination of the condition once ithas been established.

As used herein, the term "extreme aggression" shall refer to a conditioncharacterized by aggression that is so extreme that it interferes withthe individual's daily functions, relationships, and may threaten thesafety of the individual, for example in a situation in which violentsuicide is contemplated. The extreme aggression which may be treatedusing the method claimed herein shall be independent of a psychoticcondition and not directly related to the consumption of a drug or othersubstance.

The results of pharmacological studies show that olanzapine hasmuscarinic cholinergic receptor activity. The compound is active at thedopamine D-1 and D-2 receptors as indicated by an IC50 of less than 1 uMin the 3H-SCH233390 (Billard, et al. Life Sciences 35:1885 (1984)) andthe 3H spiperone (Seeman et al Nature 216:717 (1976)) binding assaysrespectively. Further, olanzapine is active at the 5-HT-2 receptor and5-HT1C receptor. The complex pharmacological profile of the compoundprovides a medicament which can be useful for the treatment of extremeaggression.

The usefulness of the compound for treating extreme aggression can besupported by the following studies as described.

Clinical observations.

A double-blind multicenter clinical trial was designed to assess thesafety and efficacy of olanzapine. Patients were randomized toolanzapine or placebo. The results of the study suggest that olanzapinecan be useful for the treatment of excessive aggression.

Olanzapine is effective over a wide dosage range, the actual doseadministered being dependent on the condition being treated. Forexample, in the treatment of adult humans, dosages of from 5 to 20 mgper day may be used. A once a day dosage is normally sufficient,although divided doses may be administered. For treatment of extremeaggression, a dose range of from 5 to 20 mg per day is suitable.Radiolabelled olanzapine, can be detected in the saliva and thus thecompound can potentially be monitored in patients to assess compliance.

A preferred formulation of the invention is a solid oral formulationcomprising from about 1 to about 20 mg or 1 to 10 mg of olanzapine as aneffective amount of the active ingredient.

Most preferably, the solid oral formulation is contained in packagingmaterials which protect the formulation from moisture and light. Forexample, suitable packaging materials include amber colored high densitypolyethylene bottles, amber colored glass bottles, and other containersmade of a material which inhibits the passage of light. Most preferably,the packaging will include a desiccant pack. The container may be sealedwith an aluminum foil blister to provide the desired protection andmaintain product stability.

Olanzapine will normally be administered orally or by injection and, forthis purpose, it is usually employed in the form of a pharmaceuticalcomposition.

Accordingly, pharmaceutical compositions comprising olanzapine, asactive ingredient associated with a pharmaceutically acceptable carriermay be prepared. In making the compositions of the inventionconventional techniques for the preparation of pharmaceuticalcompositions may be used. For example, the active ingredient willusually be mixed with a carrier, or diluted by a carrier, or enclosedwithin a carrier which may be in the form of a capsule, sachet, paper orother container. When the carrier serves as a diluent, it may be solid,semi-solid or liquid material which acts as a vehicle, excipient ormedium for the active ingredient. The active ingredient can be adsorbedon a granular solid container for example in a sachet. Some examples ofsuitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol,starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin,syrup, methyl cellulose, methyl- and propyl-hydroxy-benzoate, talc,magnesium stearate or mineral oil. The compositions of the inventionmay, if desired, be formulated so as to provide quick, sustained ordelayed release of the active ingredient after administration to thepatient.

Depending on the method of administration, the compositions for thetreatment of central nervous system conditions may be formulated astablets, capsules, injection solutions for parenteral use, gel orsuspension for transdermal delivery, suspensions or elixirs for oral useor suppositories. Preferably the compositions are formulated in a unitdosage form, each dosage containing from 5 to 20 mg, of the activeingredient.

Olanzapine can be useful for the management of excessive aggression forveterinary science purposes. Most preferredly, the veterinary patient isa mammal. For animal health purposes, olanzapine can be administered asa feed additive.

The materials for the present invention can be purchased or prepared bya variety of procedures well known to those of ordinary skill in theart. Olanzapine can be prepared as described by Chakrabarti in U.S. Pat.No. 5,229,382 ('382), herein incorporated by reference in its entirety.Further, the following preparations illustrate a method for preparing ofthe especially preferred Form II olanzapine polymorph.

Compound characterization methods include, for example, x-ray powderpattern analysis, thermogravimetric analysis (TGA), differentialscanning calorimetery (DSC), titrametric analysis for water, and H¹ -NMRanalysis for solvent content.

The following examples are provided for purposes of illustration and arenot to be construed as limiting the scope of the claimed invention.

Preparation 1 Technical Grade olanzapine ##STR2##

In a suitable three neck flask the following was added:

Dimethylsulfoxide (analytical): 6 volumes

Intermediate 1: 75 g

N-Methylpiperazine (reagent): 6 equivalents

Intermediate 1 can be prepared using methods known to the skilledartisan. For example, the preparation of the Intermediate 1 is taught inthe '382 patent.

A sub-surface nitrogen sparge line was added to remove the ammoniaformed during the reaction. The reaction was heated to 120° C. andmaintained at that temperature throughout the duration of the reaction.The reactions were followed by HPLC until≦5% of the intermediate 1 wasleft unreacted. After the reaction was complete, the mixture was allowedto cool slowly to 20° C. (about 2 hours). The reaction mixture was thentransferred to an appropriate three neck round bottom flask and waterbath. To this solution with agitation was added 10 volumes reagent grademethanol and the reaction was stirred at 20° C. for 30 minutes. Threevolumes of water was added slowly over about 30 minutes. The reactionslurry was cooled to zero to 5° C. and stirred for 30 minutes. Theproduct was filtered and the wet cake was washed with chilled methanol.The wet cake was dried in vacuo at 45° C. overnight. The product wasidentified as technical olanzapine.

Yield: 76.7%; Potency: 98.1%

Preparation 2 Form II olanzapine polymorph

A 270 g sample of technical grade2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepinewas suspended in anhydrous ethyl acetate (2.7 L) . The mixture washeated to 76° C. and maintained at 76° C. for 30 minutes. The mixturewas allowed to cool to 25° C. The resulting product was isolated usingvacuum filtration. The product was identified as Form II using x-raypowder analysis.

Yield: 197 g.

The process described above for preparing Form II provides apharmaceutically elegant product having potency≧97%, total relatedsubstances<0.5% and an isolated yield of>73%.

EXAMPLE 1

A portion of the hydroxypropyl cellulose was dissolved in purified waterto form a solution for granulation. The remaining hydroxypropylcellulose (total of 4.0% w/w final tablet weight), which was an extrafine grade, was combined with the olanzapine (1.18% w/w), lactose(79.32% w/w) and a portion of the crospovidone (5% w/w) in a high sheargranulator. All ingredients were security sieved prior to addition anddry blended in the granulator. This mixture was then granulated with thehydroxypropyl cellulose solution in the high shear granulator. Thegranulation was wet sized using standard methods. The wet granulationwas then dried in a fluidized bed dryer and sized. The material was thenadded to a tumble bin mixer.

The running powders consisting of microcrystalline cellulose (granular)(10% w/w), magnesium stearate (0.5% w/w), and the remainder of thecrospovidone were added to the sized granulation. The mixture wasblended and compressed with the appropriate tooling on tabletcompression equipment.

Subcoating:

Hydroxypropyl methylcellulose (10% w/w) was mixed with purified water toform a solution. Core tablets were divided into approximately equalsections and spray coated with the hydroxypropyl methylcellulosesolution. The operation was performed in a perforated coating pan.

Coating of Core Tablets:

Color Mixture White (hydroxypropyl methylcellulose, polyethylene glycol,polysorbate 80, and titanium dioxide) was mixed with purified water toform the coating suspension. Subcoated tablets were divided intoapproximately equal sections and spray coated with the coatingsuspension described above. The operation was performed in a perforatedcoating pan.

The coated tablets were lightly dusted with carnauba wax and imprintedwith appropriate identification.

What is claimed is:
 1. A method for treating excessive aggression in amammal, wherein the mammal is not clinically diagnosed with a psychoticcondition comprising administering an effective amount of olanzapine, ora pharmaceutically acceptable salt or solvate thereof, to such mammal.2. A method of claim 1 wherein the effective amount is from about 2.5 toabout 30 mg per day.
 3. A method of claim 1 wherein the olanzapine isForm II olanzapine polymorph.
 4. A method of claim 1 wherein the mammalis a human.
 5. A method of claim 2 wherein the mammal is a human.
 6. Amethod of claim 3 wherein the mammal is a human.